Table 1.
Strategies to target metabolic enzymes for treatment of heart failure and cancer.
| Pathway | Effect | Compound(s) | Target(s) | Rationale | Cancer field | Cardiovascular field |
|---|---|---|---|---|---|---|
| GLUCOSE OXIDATION | ||||||
| Inhibition | WZB117 | GLUT1 | Inhibition of glucose uptake; limiting nutrient supply | Preclinical data only (128, 129) | ||
| Inhibition | MK-2206 | AKT | Inhibition of the PI3K/Akt signaling pathway and cell proliferation; induction of cell apoptosis | Phase II clinical trials (130, 131) | ||
| Inhibition | Empagliflozin, Canagliflozin | SGLT2 | Inhibition of glucose reabsorption by the kidney; limiting nutrient supply | Preclinical data only (132) | In clinical trials (133, 134, 135) | |
| Inhibition | 3-Bromopyruvate, 2-deoxyglucose methyl jasmonate dichloroacetate, clotrimazole and bifonazole, and some traditional Chinese medicinal plants | HK-II | Inhibition of glycolysis to decrease cell growth and survival | Clinical and preclinical data with unacceptable toxicity observed (136) | ||
| Inhibition | AR-C155858, AZD3965 | MCT1, 2 or 4 | Inhibition of lactate release, thus promoting increased mitochondrial metabolism; limiting cell growth and survival in cells with upregulated glycolysis and limited mitochondrial metabolism | Clinical and preclinical data (137, 138, 139, 140) | ||
| Activation | GLUT1 | Preclinical data only | ||||
| Activation | Dichloroacetate | PDH | used for treating lactic acidosis; in clinical trials for the treatment of pulmonary arterial hypertension, metastatic solid tumors and malignant gliomas | Clinical and preclinical data (141, 142, 143, 144) | Clinical and preclinical data (45, 142, 145) | |
| Activation | GLP-1 | Glucagon analog | Activation of glucose metabolism | Approved 146, 147, 148 | ||
| Activation | HX-II | Activation of glycolysis to increase glucose metabolism | Preclinical data only (149, 150, 151) | |||
| FATTY ACID OXIDATION/ LIPID SYNTHESIS | ||||||
| Inhibition | Trimetazidine, Ranolazine | 3-KAT | Activation of glucose metabolism through inhibition of fatty acid metabolism | Approved in Europe and Asia (152, 153) | ||
| Inhibition | Etomoxir, Oxfenicine, Perhexiline | CPT1-inhibitor | Activation of glucose metabolism through inhibition of fatty acid transport | In clinical trials (Perhexiline); retired due to hepatotoxicity (etomoxir) | Tested in clinical trials; retired due to hepatotoxicity (Etomoxir); limited clinical trials (Oxfenicine, Perhexiline) (154, 155) | |
| Inhibition | TVB-2640 | FASN | FASN is a rate limiting enzyme in de novo lipogenesis; | Clinical and preclinical data (137) | Preclinical data only (156, 157) | |
| Inhibition | GRK2 | GRK2 enhances the ERK cascade and promotes partial inactivation of PPARG and FASN inhibition | Preclinical data only (158) | |||
| Inhibition | ETC-1002; BMS303141; SB 204990 | ACL | ACL catalyzes the conversion of citrate to acetyl-CoA, and is important for de novo lipogenesis | Preclinical data only (159) | ||
| Activation | ND-630; ND-646; MK-4074 | ACC | ACC catalyzes the irreversible carboxylation of acetyl-CoA to malonyl-CoA; ACC inhibition stimulates FAO | Preclinical data only (160) | Preclinical data only (161, 162) | |
| Activation | Fenofibrate | PPARα | PPARα agonist with antihyperlipidemic activity by activation of lipoprotein lipase and reduction of the production of apoprotein C-III | Approved (163, 164) | ||
| Activation | Metformin | ETC complex I | Reduction of plasma levels for insulin and IGF-1; Activation of AMPK and inhibition of mTORC1 | Approved in T2DM (165, 166) | ||
| NUCLEIC ACID SYNTHESIS | ||||||
| Inhibition | Methotrexate; pemetrexed | DHFR | Inhibition of DHFR resulting in inhibition of purine nucleotide and thymidylate synthesis; immunosuppressant activities | Approved in various cancer (CVD side effects) | ||
| Inhibition | 5-Fluorouracil | TYMS | Converted to active F-UMP; replacing uracil and inhibits RNA processing | Approved in various cancer (CVD side effects) | ||
| Inhibition | Hydroxyurea | RNR | RNR required to convert ribonucleoside diphosphate into deoxyribonucleoside diphosphates | Approved in leukemia (CVD side effects) | ||
| Inhibition | Gemcitabine; Fludarabine | RNR; DNA polymerase | Deoxycytidine analogs are onverted to dFdCDP and dFDCTP which compete with dCTP; prevents nucleotide incorporation | Approved in various cancer (CVD side effects) | ||
| Inhibition | TKTL1; GAPDH | TKTL1 allows non-oxidative ribose synthesis; GAPDH required for oxidative riobose synthesis and NADPH provision | Preclinical data only | Preclinical data only | ||
| AMINO ACID METABOLISM | ||||||
| Inhibition | Asparaginase | Asparagine availability | Asparaginase hydrolyzes L-aspargine, resulting in inhibition of protein synthesis, cell cyle arrest and apoptosis | Approved in leukemia (CVD side effects) | ||
| Inhibition | BPTES;CD-839 | Glutamine availability | GLS1 inhibition; induces apoptosis, growth arrest and/or autophagy | Preclinical data only | Preclinical data only | |
ACC, acetyl-CoA carboxylase; ACL, AKT, protein kinase B; ATP citrate lyase; AMPK, AMP-activated protein kinase; CPT1, carnitine palmitoyltransferase 1; DHFR, dihydrofolate reductase; ERK, extracellular signal-regulated kinase; ETC, Electron transport chain, FASN, fatty acid synthase; GAPDH, glucose-6-phosphate dehydrogenase; GLS, glutaminase 1; GLUT1, glucose transporter 1; GRK2, G protein-coupled receptor kinase 2; HK-II, hexokinase 2; IGF-1, Insulin-like growth factor 1; MCT, monocarboxylate transporter; mTOR, mechanistic target of rapamycin; PDH, pyruvate carboxylase complex; PPAR, peroxisome proliferator-activated receptor; RNR, ribonucleotide reductase; SGLT2, Sodium-glucose co-transporter 2; TKTL1, transketolase-like protein 1; TYMS, thymidylate synthase.